The long-term objective of our work is to understand the in vivo regulation of natural killer (NK) cell proliferation and homeostasis during viral infections. NK cells are innate lymphocytes that participate in tumor surveillance and play a critical role in early anti-pathogen host defense. They are particularly important in host resistance to large DNA viruses, such as cytomegalovirus (CMV). Indeed, humans with selective NK cell deficiencies suffer from recurrent, often fatal, herpesvirus infections, includin CMV. NK cells are stimulated by cytokines elicited early during viral infections, as well as by direct recognition of infected cells through activation receptors. In C57BL/6 mice, the NK cell activation receptor that mediates resistance to murine cytomegalovirus (MCMV) is Ly49H. Ly49H recognition of its ligand on infected cells and subsequent signaling through its adaptor molecule DAP12 stimulates NK cell production of immunomodulatory cytokines and killing of infected cells. In addition to these effector functions, NK cells rapidly proliferate during viral infections. We have shown that the viral-induced proliferative response occurs in three distinct phases, including early nonspecific NK cell proliferation, preferential proliferation of NK cells tat are able to recognize infected cells, and cessation of proliferation with contraction of the expanded NK cell population. Furthermore, we have evidence that a and ?d T cells actively participate in the resolution of viral-induced NK cell proliferation. Although the basic regulationof progression through the cell cycle is well understood (e.g., the role of cell division cycle 25 [Cdc25] phosphatases in removing inhibitory phosphates from CDK/cyclin complexes), the mechanisms regulating NK cell proliferation and homeostasis remain poorly characterized. Building on observations made in the previous funding period, we propose to investigate the role of distinct Cdc25 phosphatases in facilitating non-specific and preferential NK cell proliferation during MCMV infection and to delineate the contributions of T cells and apoptosis to the resolution of viral-induced NK cell activation and proliferation. We contend that a clearer understanding of the in vivo regulation of NK cell proliferation during viral infections will have broad translational implications and may lead to novel therapeutic interventions to modulate NK cell responses to tumors and viruses.